Host factors determining progression to AIDS in lentiviral infection remain poorly understood. Sooty mangabeys are one of the Old World monkey species identified that are naturally infected in the wild with simian immunodeficiency virus (SIVsmm) but do not develop AIDS. The same virus SIVsmm, when transmitted to rhesus macaques produces simian AIDS. To understand the correlates of host immunity conferring protection against the consequences of SIV-infection, we have analyzed SIV-specific CTL responses in sooty mangabeys with both natural and experimentally acquired SIV infection. The sooty mangabeys are housed at the Yerkes Primate Research Center, Atlanta. Four sooty mangabeys with chronic natural SIV infection and high plasma viral loads were initially studied. Autologous B-LCL infected with recombinant vaccinia-SIV constructs were used for in vitro stimulation as well as target cells. SIV-specific CTL activity was measured after 10-12 days of in vitro stimulation, in a standard 51chromium release assay. Using this methodology, no CTL activity was not detected in PBMC from any of the four animals. However, high levels of lysis of allogeneic B-LCL were consistently observed, indicating that the ability of their CD8+ lymphocytes to respond to and lyse cells expressing foreign antigens is intact. We have also analyzed the kinetics of viral replication and SIV-specific CTL responses in rhesus macaques and sooty mangabeys with experimental SIV infection. A SIV-specific CTL response was detected in both the sooty mangabey and the rhesus macaque after 12 to 16 weeks of infection. The sooty mangabey mounted an initial strong anti-pol response followed subsequently by a vigorous anti-gag, pol and env response. Unlike naturally infected mangabeys, the SIV viremia levels as assessed by bDNA analysis were lower in this animal and had come down by week 4 of infection. The study is ongoing and a second pair of animals has been infected recently.